1. Field
This disclosure relates to co-crystals of nitrogen-containing heterocycles with carboxylic acids for the treatment of diseases.
2. Description of the Related Art
Neamati et al. reported nitrogen-containing heterocycles for the treatment of cancer and disorders associated with angiogenesis function (see U.S. patent application Ser. No. 11/265,593; Grande et al., “Synthesis and Antitumor Activities of a Series of Novel Quinoxalinhydrazines,” Bioorg. Med. Chem. 15, 288-94 (2007), which are expressly incorporated herein by reference in their entireties). These nitrogen-containing heterocycles include compounds of Formula II:
wherein R is H, alkyl, or halogen; R′ is H, alkyl, or halogen; X is CH or N; and Y comprises a homocyclic or heterocyclic ring, wherein Y is 3-, 5-, or 6-pyrazinyl or 3-, 4-, 5-, or 6-pyridinyl when R is H, R′ is H, X is CH, and Y is pyrazinyl or pyridinyl. One example reported therein is N′-(7-fluoropyrrolo[1,2a]quinoxalin-4-yl)pyrazine-2-carbohydrazide (“NVX-144”):

Aakeröy et al. discuss the advantages of co-crystals of nitrogen-containing heterocycles with carboxylic acids over the corresponding salts (see Aakeröy et al., “Cocrystal or Salt: Does It Really Matter?” Mol. Pharmaceutics, 4, 317-22 (2007), the entirety of which is expressly incorporated herein by reference). They report that salt formation, resulting from proton transfer from the acid to the base, is almost ten times more likely to result in a lattice with an unpredictable chemical (solvate) or stoichiometric composition than is molecular co-crystal formation, where no proton transfer occurs. They conclude that the resultant simplification of structure prediction and targeted supramolecular synthesis should allow increased diversity of accessible solid forms of drug substances that exhibit desirable properties.